The overall goal of this project is to investigate if blockade of vascular endothelial growth factor (VEGF) in combination with conventional chemotherapy or hormonal therapy could be a new innovative treatment regimen for metastatic prostate cancer. We have shown that treatment (i.p.) with the monoclonal antibody A4.6.1, specific for human VEGF, completely inhibits neovascularization of micro tumors from a variety of human tumor cell lines including the human prostatic carcinoma cell line DU 145. Treatment with A4.6.1 suppresses tumor growth of these cell lines to the extent that there is complete inhibition after the initial pre-vascular angiogenesis independent growth phase. However, viable dormant tumor seedlings remain. Those data were all derived using established human tumor cell lines, however in the present application, we propose to use advanced human prostate cancer transferred directly from surgical samples from patents to test our hypothesis. In Our first aim we will use the dorsal skinfold chambers in nude mice to investigate the angiogenic activity and growth pattern as well as the efficacy of A4.6.1 to inhibit angiogenesis of two androgen and two androgen-independent early prostate cell lines obtained directly from tissue samples from patients. Results from this aim will answer the question to what extent effective blockade of VEGF alone inhibits prostate cancer angiogenesis in vivo. Our second aim is to use the same antibody, in combination with conventional chemotherapy to address the question if conventional chemotherapy can eradicate the dormant tumor seedlings which remain after effective anti-angiogenic treatment. We have chosen to combine anti-VEGF with Estramustine and Etoposide. Our third aim is to evaluate combination of hormonal treatment with effective anti-VEGF treatment. The proposed studies provide a systematic approach to further the understanding of the effect anti-VEGF therapy in advanced human prostate cancer and to clarify if blockade of VEGF in combination with conventional chemotherapeutic or hormonal agents could be advantageous as a new innovative treatment modality for treatment of metastatic prostate cancer, which for today there is no cure.